The long term objective of this proposal is to learn the etiology and pathogenesis of neurofibrillary tangle of paired helical filaments (PHF) which is the most striking lesion in dementias of the Alzheimer type and in several conditions with mental retardation. The concentration of this lesion correlates directly to the degree of dementia. The studies proposed in this application are designed to determine the biochemical origin of the PHF. We have developed a method for isolation of highly purified preparations of PHF. We will purify PHF from autopsied Alzheimer brains to near homogeneity, identify its protein subunit/s, purifiy each of these proteins and in comparison with purified normal neurofibrous proteins characterize each PHF protein a) chemically by peptide maps, amino-terminal and carboxy-terminal analysis and amino acid composition, and b) immunochemically and immunocytochemically by Ouchterlony double diffusion test, immunobinding by 125I Protein A method on strips of polyacrylamide slab gels, and immunolabeling with and without immunoabsorption at light microscopic level by immunofluorescence and peroxidase-antiperoxidase (PAP) methods, and electron microscopic level by PAP and immunoperoxidase methods. We will also purify PHF from cases of Guam Parkinsonism dementia complex and Down syndrome (adult cases) and isolate PHF proteins and characterize these in comparison with PHF proteins from cases of Alzheimer disease, and study the immunocytochemical reaction of antisera to PHF proteins from Alzheimer brains with a) neurofibrillary changes of PHF in other human conditions such as normal aging, senile dementia, Guam Parkinsonism dementia, dementia pugilistica, Down syndrome, Hallerworden-Spatz disease and subacute sclerosing panencephalitis, b) neurofibrillary accumulation of 15 nm fibers in human diseases such as Steele-Richardson-Olszewski syndrome and c) neurofibrillary accumulation of 10 nm filaments in human disorders such as sporadic motor neuron disease, vincristine neuropathy and infantile neuroaxonal dystrophy, and in experimental animal conditions such as colchicine-induced neurofibrillary changes in rabbits.